The present invention relates to the area of dipeptidyl peptidase-IV inhibition and, more particularly, relates to certain N-(substituted glycyl)-2-cyanopyrrolidines, pharmaceutical compositions containing said compounds, and the use of said compounds in inhibiting dipeptidyl peptidase-IV.
1. Background of the Invention
Dipeptidyl peptidase-IV (DPP-IV) is a serine protease which cleaves N-terminal dipeptides from a peptide chain containing, preferably, a proline residue in the penultimate position. Although the biological role of DPP-IV in mammalian systems has not been completely established, it is believed to play an important role in neuropeptide metabolism, T-cell activation, attachment of cancer cells to the endothelium and the entry of HIV into lymphoid cells.
Likewise, it was discovered that DPP-IV is responsible for inactivating glucagon-like peptide-1 (GLP-1). Since GLP-1 is a major stimulator of pancreatic insulin secretion and has direct beneficial effects on glucose disposal, DPP-IV inhibition appears to represent an attractive approach for treating non-insulin-dependent diabetes mellitus (NIDDM).
2. Description of the Prior Art
WO95/15309 discloses certain peptide derivatives which are inhibitors of DPP-IV and, therefore, are useful in treating a number of DPP-IV mediated processes.
Archives of Biochemistry and Biophysics, Vol. 323, No. 1, pgs. 148-154 (1995) discloses certain aminoacylpyrrolidine-2-nitriles which are useful as DPP-IV inhibitors.
Bioorganic and Medicinal Chemistry Letters, Vol. 6, No. 10, pgs. 1163-1166 (1996) discloses certain 2-cyanopyrrolidines which are inhibitors of DPP-IV.
European Journal of Medicinal Chemistry, Vol. 32, pgs. 301-309 (1997) discloses certain pyrrolidides which are useful as DPP-IV inhibitors.
WO98/19998 discloses certain N-substituted-2-cyanopyrrolidines which are useful as DPP-IV inhibitors.
Biochemistry, Vol. 38, pgs. 11597-11603 (1999) discloses (1-[[[[2-[(5-cyanopyridin-2-yl)amino]ethyl]amino]acetyl]-2-cyano-(S)-pyrrolidine) as a slow-binding inhibitor of DPP-IV.
The present invention provides new DPP-IV inhibitors which are effective in treating conditions mediated by DPP-IV inhibition. More particularly, the present invention relates to certain N-(substituted glycyl)-2-cyanopyrrolidines which inhibit DPP-IV. In addition, the present invention provides pharmaceutical compositions useful in inhibiting DPP-IV comprising a therapeutically effective amount of a certain N-(substituted glycyl)-2-cyanopyrrolidine. Moreover, the present invention provides a method of inhibiting DPP-IV comprising administering to a mammal in need of such treatment a therapeutically effective amount of a certain N-(substituted glycyl)-2-cyanopyrrolidine.
The essence of the instant invention is the discovery that certain N-(substituted glycyl)-2-cyanopyrrolidines are useful in inhibiting DPP-IV. In one embodiment, the present invention provides compounds of formula I: 
where Y is:
a) a group of the formula 
where R is an unsubstituted pyridine or pyrimidine ring; a pyridine or pyrimidine ring which is mono- or independently di-substituted by halo, trifluoromethyl, cyano, nitro or C1-6alkyl; unsubstituted benzoyl; a benzoyl group which is mono- or di-substituted by halo or C1-6alkyl; C1-6alkylcarbonyl; di-C1-6alkylaminocarbonyl; unsubstituted phenylaminocarbonyl; or a phenylaminocarbonyl group which is mono- or di-substituted on the phenyl ring by halo or C1-6alkyl;
b) a group of the formula 
where R1 is an unsubstituted pyridine, pyrimidine or phenyl ring; a pyridine, pyrimidine or phenyl ring which is mono- or independently di-substituted by halo, trifluoromethyl, cyano, nitro or C1-6alkyl; an unsubstituted phenylsulfonyl group; a phenylsulfonyl group which is mono- or di-substituted on the phenyl ring by halo, trifluoromethyl, cyano, nitro or C1-6alkyl; unsubstituted benzoyl; a benzoyl group which is mono- or di-substituted by halo or C1-6alkyl; C1-6alkylcarbonyl; thienyl sulfonyl; unsubstituted benzothiazole; or a benzothiazole group which is substituted on the phenyl ring by halo or C1-6alkyl;
c) a group of the formula 
where R2 is an unsubstituted phenyl ring; or a phenyl ring which is mono- or di-substituted by halo or C1-6alkyl;
d) a group of the formula 
where R3 is an unsubstituted phenylsulfonyl group; a phenylsulfonyl group which is mono- or di-substituted on the phenyl ring by halo, trifluoromethyl, cyano, nitro or C1-6 alkyl; C1-6alkylcarbonyl; di-C1-6alkylaminocarbonyl; C3-8 cycloalkylcarbonyl; unsubstituted benzoyl; a benzoyl group which is mono- or di-substituted by halo or C1-6alkyl; unsubstituted phenylaminocarbonyl; phenylaminocarbonyl which is mono- or di-substituted on the phenyl ring by halo or C1-6alkyl; a substituted thiazole ring; or a phenyl-substituted thiazole ring wherein the phenyl ring is mono- or di-substituted by halo or C1-6alkoxy;
e) a (4-pentylbicyclo[2.2.2]oct-1-yl) amine group; or
f) a group of the formula 
where R4 is an unsubstituted phenyl ring; or a phenyl ring which is mono- or di-substituted by halo, trifluoromethyl, cyano, nitro or C1-6alkyl; or an acid addition salt thereof.
Preferred compounds are those of formula Ia: 
where Yxe2x80x2 is:
a) a group of the formula 
where Rxe2x80x2 is an unsubstituted pyridine or pyrimidine ring; a pyridine or pyrimidine ring which is mono- or independently di-substituted by halo, trifluoromethyl or cyano; unsubstituted benzoyl; a benzoyl group which is monosubstituted by halo or C1-6alkyl; C1-6alkylcarbonyl; di-C1-6alkylaminocarbonyl; unsubstituted phenylaminocarbonyl; or a phenylaminocarbonyl group which is monosubstituted on the phenyl ring by halo or C1-6alkyl;
b) a group of the formula 
where R1xe2x80x2 is an unsubstituted pyridine, pyrimidine or phenyl ring; a pyridine, pyrimidine or phenyl ring which is monosubstituted by halo, trifluoromethyl, cyano, nitro or C1-6alkyl; an unsubstituted phenylsulfonyl group; a phenylsulfonyl group which is monosubstituted on the phenyl ring by halo, trifluoromethyl, cyano, nitro or C1-6alkyl; unsubstituted benzoyl; a benzoyl group which is monosubstituted by halo or C1-6alkyl; C1-6alkylcarbonyl; thienyl sulfonyl; unsubstituted benzothiazole; or a benzothiazole group which is substituted on the phenyl ring by halo or C1-6alkyl;
c) a group of the formula 
where R2xe2x80x2 is an unsubstituted phenyl ring; or a phenyl ring which is monosubstituted by halo or C1-6alkyl;
d) a group of the formula 
where R3xe2x80x2 is an unsubstituted phenylsulfonyl group; a phenylsulfonyl group which is monosubstituted on the phenyl ring by halo, trifluoromethyl, cyano, nitro or C1-6alkyl; C1-6alkylcarbonyl; di-C1-6alkylaminocarbonyl; C3-8cycloalkylcarbonyl; unsubstituted benzoyl; a benzoyl group which is monosubstituted by halo or C1-6 alkyl; unsubstituted phenylaminocarbonyl; phenylaminocarbonyl which is monosubstituted on the phenyl ring by halo or C1-6alkyl; a phenyl-substituted thiazole ring; or a phenyl-substituted thiazole ring wherein the phenyl ring is monosubstituted by halo or C1-6alkoxy;
e) a (4-pentylbicyclo[2.2.2]oct-1-yl)amine group; or
f) a group of the formula 
where R4xe2x80x2 is an unsubstituted phenyl ring; or a phenyl ring which is monosubstituted by halo, trifluoromethyl, cyano, nitro or C1-6alkyl; or an acid addition salt thereof.
More preferred compounds are those of formula Ib : 
where Yxe2x80x3 is:
a) a group of the formula 
where Rxe2x80x3 is an unsubstituted pyridine or pyrimidine ring; a pyridine or pyrimidine ring which is mono-substituted by halo, trifluoromethyl or cyano or di-substituted by halo; unsubstituted benzoyl; a benzoyl group which is mono-substituted by halo or C1-4alkyl; C1-6alkylcarbonyl; di-C1-6alkylaminocarbonyl; unsubstituted phenylaminocarbonyl; or a phenylaminocarbonyl group which is monosubstituted on the phenyl ring by halo or C1-4alkyl;
b) a group of the formula 
where R1xe2x80x3 is an unsubstituted pyridine, pyrimidine or phenyl ring; a pyridine, pyrimidine or phenyl ring which is monosubstituted by halo, trifluoromethyl, cyano, nitro or C1-4alkyl; an unsubstituted phenylsulfonyl group; a phenylsulfonyl group which is monosubstituted on the phenyl ring by halo, trifluoromethyl, cyano, nitro or C1-4alkyl; unsubstituted benzoyl; a benzoyl group which is monosubstituted by halo or C1-4alkyl; C1-6alkylcarbonyl; thienyl sulfonyl; unsubstituted benzothiazole; or a benzothiazole group which is substituted on the phenyl ring by halo or C1-4alkyl;
c) a group of the formula 
where R2xe2x80x3 is an unsubstituted phenyl ring; or a phenyl ring which is monosubstituted by halo or C1-4 alkyl;
d) a group of the formula 
where R3xe2x80x3 is an unsubstituted phenylsulfonyl group; a phenylsulfonyl group which is monosubstituted on the phenyl ring by halo, trifluoromethyl, cyano, nitro or C1-4alkyl; C1-6alkylcarbonyl; di-C1-6alkylaminocarbonyl; C3-8cycloalkylcarbonyl; unsubstituted benzoyl; a benzoyl group which is monosubstituted by halo or C1-4alkyl; unsubstituted phenylaminocarbonyl; phenylaminocarbonyl which is monosubstituted on the phenyl ring by halo or C1-4alkyl; a phenyl-substituted thiazole ring; or a phenyl-substituted thiazole ring wherein the phenyl ring is monosubstituted by halo or C1-4alkoxy;
e) a (4-pentylbicyclo[2.2.2]oct-1-yl)amine group; or
f) a group of the formula 
where R4xe2x80x3 is an unsubstituted phenyl ring; or a phenyl ring which is monosubstituted by halo, trifluoromethyl, cyano, nitro or C1-4alkyl;
or an acid addition salt thereof.
Even more preferred compounds are those of formula Ic: 
where Yxe2x80x2xe2x80x3 is:
a) a group of the formula 
where Rxe2x80x2xe2x80x3 is an unsubstituted pyridine or pyrimidine ring; a pyridine or pyrimidine ring which is monosubstituted by chloro, trifluoromethyl or cyano or disubstituted by chloro; unsubstituted benzoyl; a benzoyl group which is monosubstituted by chloro, methyl or ethyl; C1-6alkylcarbonyl; di-C1-6alkylaminocarbonyl; unsubstituted phenylaminocarbonyl; or a phenylaminocarbonyl group which is monosubstituted on the phenyl ring by chloro;
b) a group of the formula 
where R1xe2x80x2xe2x80x3 is an unsubstituted pyridine, pyrimidine or phenyl ring; a pyridine, pyrimidine or phenyl ring which is monosubstituted by chloro, trifluoromethyl or cyano; an unsubstituted phenylsulfonyl group; a phenylsulfonyl group which is monosubstituted on the phenyl ring by chloro or trifluoromethyl; unsubstituted benzoyl; a benzoyl group which is monosubstituted by chloro; C1-6alkylcarbonyl; thienyl sulfonyl; unsubstituted benzothiazole; or a benzothiazole group which is substituted on the phenyl ring by chloro;
c) a group of the formula 
where R2xe2x80x2xe2x80x3 is an unsubstituted phenyl ring; or a phenyl ring which is monosubstituted by fluoro;
d) a group of the formula 
where R3xe2x80x2xe2x80x3 is an unsubstituted phenylsulfonyl group; a phenylsulfonyl group which is monosubstituted on the phenyl ring by chloro or trifluoromethyl; C1-6alkylcarbonyl; di-C1-6alkylaminocarbonyl; C3-8cycloalkylcarbonyl; unsubstituted benzoyl; a benzoyl group which is monosubstituted by chloro; unsubstituted phenylaminocarbonyl; phenylaminocarbonyl which is monosubstituted on the phenyl ring by chloro; a phenyl-substituted thiazole ring; or a phenyl-substituted thiazole ring wherein the phenyl ring is monosubstituted by chloro or methoxy;
e) a (4-pentylbicyclo[2.2.2]oct-1-yl)amine group; or
f) a group of the formula 
where R4xe2x80x2xe2x80x3 is an unsubstituted phenyl ring; or a phenyl ring which is monosubstituted by chloro or trifluoromethyl;
or an acid addition salt thereof.
Compounds of formula I, Ia, 1b or Ic, wherein Y represents a group of formula b) and f) are preferably in the trans orientation that is represented by formulae 
In another embodiment, the instant invention provides pharmaceutical compositions useful in inhibiting DPP-IV comprising a pharmaceutically acceptable carrier or diluent and a therapeutically effective amount of a compound of formula I above, or a pharmaceutically acceptable acid addition salt thereof, preferably a compound of formula Ia above, or a pharmaceutically acceptable acid addition salt thereof, more preferably a compound of formula Ib above, or a pharmaceutically acceptable acid addition salt thereof, and even more preferably a compound of formula Ic above, or a pharmaceutically acceptable acid addition salt thereof.
In still another embodiment, the instant invention provides a method of inhibiting DPP-IV comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound of formula I above, or a pharmaceutically acceptable acid addition salt thereof, preferably a compound of formula Ia above, or a pharmaceutically acceptable acid addition salt thereof, more preferably a compound of formula Ib above, or a pharmaceutically acceptable acid addition salt thereof, and even more preferably a compound of formula Ic above, or a pharmaceutically acceptable acid addition salt thereof.
In a further embodiment, the instant invention provides a method of treating conditions mediated by DPP-IV inhibition comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound of formula I above, or a pharmaceutically acceptable acid addition salt thereof, preferably a compound of formula Ia above, or a pharmaceutically acceptable acid addition salt thereof, more preferably a compound of formula Ib above, or a pharmaceutically acceptable acid addition salt thereof, and even more preferably a compound of formula Ic above, or a pharmaceutically acceptable acid addition salt thereof.
The compounds of formula I can exist in free form or in acid addition salt form. Pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salts are preferred, although other salts are also useful, e.g., in isolating or purifying the compounds of this invention. Although the preferred acid addition salts are the hydrochlorides, salts of methanesulfonic, sulfuric, phosphoric, citric, lactic and acetic acid may also be utilized.
The compounds of the invention may exist in the form of optically active isomers or diastereoisomers and can be separated and recovered by conventional techniques, such as chromatography.
Listed below are definitions of various terms used to describe this invention. These definitions apply to the terms as they are used throughout this specification, unless otherwise limited in specific instances, either individually or as part of a larger group.
The term xe2x80x9chaloxe2x80x9d refers to chloro, fluoro, bromo or iodo.
The term xe2x80x9cC1-6alkylxe2x80x9d and the xe2x80x9cC1-6alkylxe2x80x9d portion of xe2x80x9cdi-C1-6alkylaminocarbonylxe2x80x9d refers to straight or branched chain hydrocarbon groups having 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms, more preferably 1 or 2 carbon atoms. Exemplary alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, isobutyl, pentyl, hexyl and the like.
The xe2x80x9cC1-6alkylxe2x80x9d portion of xe2x80x9cC1-6alkylcarbonylxe2x80x9d, in addition to the definition above, also refers to cyclic hydrocarbon groups, e.g. cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
The C3-8 portion of C3-8cycloalkylcarbonyl refers to e.g. cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
The bond containing the wavy line signifies the point of attachment of the xe2x80x9cYxe2x80x9d group to the glycyl-2-cyanopyrrolidine moiety.
The N-(substituted glycyl)-2-cyanopyrrolidines of the invention may be prepared, e.g., by a process which comprises coupling a reactive (2-cyanopyrrolidine)carbonylmethylene compound with an appropriate substituted amine. More particularly, the compounds of formula I may be prepared by reacting a compound of formula II 
where X is a reactive group (preferably a halogen group such as chlorine, bromine or iodine, more preferably chlorine) with a compound of formula III
Yxe2x80x94NH2xe2x80x83xe2x80x83III
where Y is as defined above, and recovering the resultant compound of formula I in free form or in acid addition salt form.
The coupling may be effected by reacting the compound of formula II with 1 to 3 equivalents, preferably 3 equivalents, of a primary amine compound of formula III. The reaction is conveniently conducted in the presence of an inert, organic solvent, preferably a chlorinated, aliphatic hydrocarbon such as methylene chloride or a cyclic ether such as tetrahydrofuran, at a temperature of from about 0xc2x0 to about 35xc2x0 C., preferably from about 0xc2x0 to about 25xc2x0 C.
The compounds of the invention may be isolated from the reaction mixture and purified in conventional manner, e.g., by chromatography.
The starting compounds of formula II may be prepared by the following two-step reaction: 
where X is as defined above.
Step 1 involves the reaction of the L-prolinamide compound of formula IV with a slight molar excess of a haloacetylhalide such a chloroacetylchloride or bromoacetylbromide and a base, e.g., an inorganic base such as potassium carbonate or an organic base such as triethylamine. The reaction is conveniently conducted in the presence of an inert, organic solvent, preferably a cyclic ether such as tetrahydrofuran or a chlorinated aliphatic hydrocarbon such as methylene chloride at a temperature of from about 0xc2x0 to about 25xc2x0 C., preferably from about 0xc2x0 to about 15xc2x0 C.
Step 2 concerns the dehydration of the compound prepared in Step 1, i.e, a en compound of formula V, with 1 to 2 equivalents of trifluoroacetic anhydride (TFAA) to obtain a compound of formula II. The dehydration is conveniently conducted in the presence of an inert, organic solvent, preferably a cyclic ether such as tetrahydrofuran or a chlorinated, aliphatic hydrocarbon such as methylene chloride, at a temperature of from about 0xc2x0 to about 25xc2x0 C., preferably from about 0xc2x0 to about 15xc2x0 C.
Insofar as their preparation is not particularly described herein, the primary amine compounds of formula III are either known or may be prepared from known compounds in a known manner or analogously to known methods or analogously to methods described in the Examples. For example, the amine compounds of formula III may be prepared by reacting excess 1,2-diamino-2-methylpropane with the appropriate chloropyridine, chloropyrimidine, acid chloride, carbamoyl chloride or sulfonyl chloride. Thus, 2-[(5-chloro-2-pyridinyl)amino]-1,1-dimethylamine can be prepared by refluxing 2,5-dichloropyridine in excess 1,2-diamino-2-methylpropane for a period of between 2 and 12 hours. The following amines can be prepared in a similar fashion: a) 2-[(5-cyano-2-pyridinyl)amino]-1,1-dimethylethylamine from 5-cyano-2-chloropyridine, b) 2-[(5-trifluoromethyl-2-pyridinyl)amino]-1,1-dimethylethylamine from 5-trifluoromethyl-2-chloropyridine, c) 2-[(3-chloro-2-pyridinyl)amino]-1,1-dimethylethylamine from 2,3-dichloropyridine, d) 2-[(3,5-dichloro-2-pyridinyl)amino]-1,1-dimethylethylamine from 2,3,5-trichloropyridine, and e) 2-[(3-trifluoromethyl-2-pyridinyl)amino]-1,1-dimethylethylamine from 2-chloro-3-trifluoromethyl pyridine. The following amines can be prepared in a similar fashion at room temperature or lower, in the presence of an organic solvent, such as tetrahydrofuran and a base, such as potassium carbonate: a) 2-[(4-methylbenzoyl)amino]-1,1-dimethylethylamine from p-toluoyl chloride, b) 2-[(4-trifluoromethyl-2-pyridinyl)amino-1,1-dimethylethylamine from 2-chloro-4-(trifluoromethyl)pyridine, c) 2-[(2,2-dimethyl-1-oxopropyl)amino]-1,1-dimethylethyl]amine from trimethylacetyl chloride, d) 2-[(4-chlorobenzoyl)amino]-1,1-dimethylethylamine from 4-chlorobenzoyl chloride, e) 2-[[(diisopropylamino)carbonyl]amino]-1,1-dimethylethylamine from diisopropylcarbamylchloride, and f) 2-[[[(4-chlorophenyl)amino]carbonyl]amino]-1,1-dimethylethylamine from 4-chlorophenyl isocyanate. In addition, the amine compounds of formula III may be prepared by reacting excess trans-1,4-diaminocyclohexane with the appropriate chloropyridine, chloropyrimidine, acid chloride, carbamoyl chloride, chlorobenzothiazole or sulfonyl chloride. For example, 1-[4-[(5-cyano-2-pyridinyl)amino]cyclohexylamine can be prepared from 5-cyano-2-chloropyridine and two equivalents of 1,4-diaminohexane at room temperature in the presence of an organic solvent, such as dioxane and a base, such as potassium carbonate, for a period of between 2 and 48 hours. The following amines can be prepared in a similar fashion: a) 1-[4-[(phenylsulfonyl)amino]cyclohexyl]amine from phenylsulfonyl chloride, b) 1-[4-(benzoylamino)cyclohexyl]amine from benzoylchloride, c) 1-[4-[[(4-trifluoromethyl)-2-pyrimidinyl]amino]cyclohexyl]amine from 2-chloro-4-(trifluoromethyl)pyrimidine, d) 1-[4-[[(3-trifluoromethyl)-2-pyridinyl)amino]cyclohexyl]amine from 3-trifluoromethyl-2-chloropyridine, e) 1-[[4-[(4-chlorophenyl)sulfonyl]amino]cyclohexyl]amine from 4-chlorobenzenesulfonyl chloride, f) 1-[4-[(5-trifluoromethyl-2-pyridinyl)amino]cyclohexyl]amine from 5-trifluoromethyl-2-chloropyridine, g)1-[4-[(2-chloro-4-pyrimidinyl)amino]cyclohexyl]amine from 2,4dichloropyrimidine, h) 1-[4-[(4-chlorobenzoyl)amino]cyclohexyl]amine from 4-chlorobenzoyl chloride, i) 1-[4-[(2,2-dimethyl-1-oxopropyl)amino]cyclohexyl]amine from trimethylacetyl chloride, j) 1-[4-[(2-benzothiazolyl)amino]cyclohexyl]amine from 2-chlorobenzothiazole in THF at reflux for 18 hr., k) 1-[4-[(4-cyanophenyl)amino]cyclohexyl]amine from 4-aminobenzonitrile in DMF at 100xc2x0 C. for 48 hours, l) 1-[4-[(cyclohexylcarbonyl)amino]cyclohexyl]amine from cyclohexanecarbonyl chloride, m) 1-[4-[(5-chloro-2-benzothiazolyl)amino]cyclohexyl]amine from 5-chloro-2-mercaptobenzothiazole at  greater than 200xc2x0 C. for 1 hr in 1,4-diaminocyclohexane as solvent, n) 1-[4-[(4-trifluoromethyl)phenyl]sulfonyl]amino]cyclohexyl]amine from 4-(trifluoromethyl)benzenesulfonyl chloride, and o) 1-[4-[[(2-thienyl)sulfonyl]amino]cyclohexyl]amine from 2-(thienyl)sulfonyl chloride. Moreover, the amine compounds of formula III may be prepared by reacting trans-4-aminocyclohexanol with the appropriate chloropyridine, chloropyrimidine, acid chloride, carbamoyl chloride, chlorobenzothiazole or sulfonyl chloride. For example, 1-[4-[4-(trifluoromethyl)phenoxy]cyclohexyl]amine can be prepared by slowly adding 4-fluorobenzotrifluoride (1.25 equivalents) to a suspension of sodium hydride (3.00 equivalents) and trans-4-aminocyclohexanol (1.00 equivalent) in DMF. The desired amine is obtained after stirring for three hours at 60xc2x0 C. and then at room temperature for 18 hours. The following amines can be prepared in a similar fashion: a) 1-[4-[4-(chlorophenoxy)]cyclohexyl]amine from 1-chloro-4-fluorobenzene, b) 1-[4-[(3-trifluoromethyl)phenoxy]cyclohexyl]amine from 1-fluoro-3-trifluoromethylbenzene, and c) 1-[4-(3-chlorophenoxy)cyclohexyl]amine from 1-chloro-3-fluorobenzene. Furthermore, the amine compounds of formula III may be prepared by reacting tert-butyl-4-piperidylcarbamate with isocyanates and carbamyl chlorides followed by tert-butylcarbamate deprotection. For example, 1-[1-[[(4-chlorophenyl)amino]carbonyl]-4-piperidinyl]amine, monohydrochloride can be prepared with the addition of 4-chlorophenyl isocyanate (1.00 equivalent) to a solution of tert-butyl-4-piperidylcarbamate (1.00 equivalent) in tetrahydrofuran followed by stirring at ice water temperature for two hours, followed by deprotection of the resulting urea (hydrogen chloride in ethyl acetate). 1-[1-[(diisopropylamino)carbonyl]-4-piperidinyl]amine can be prepared in a similar fashion from diisopropylcarbamyl chloride. Still further, the amine compounds of formula III may be prepared from ted-butyl-4-piperidylcarbamate to provide 1-[1-[4-(4-Z-phenyl)-2-thiazolyl]-4-piperidinyl]amines where Z is either H, Cl or methoxy. For example, 1-[1-[4-(4-methoxyphenyl)-2-thiazolyl]-4-piperidinyl]amine, monohydride can be prepared with the addition of benzoyl isothiocyanate (1.00 equivalent) to a solution of tert-butyl-4-piperidylcarbamate (1.00 equivalent) in tetrahydrofuran followed by stirring at room temperature for two hours. Hydrolysis of the resulting benzoyl isothiocyanate (K2CO3/H2O, reflux for 24 h) provides the thiourea which is reacted with 1.00 equivalent of 2-bromo-4xe2x80x2-methoxyacetophenone (EtOH, NEt3 at reflux for 2 hours). Deprotection of the t-butylcarbamate protecting group (hydrogen chloride in ethyl acetate) provides the target amine monohydrochloride. The following amines can be prepared in a similar fashion: a) 1-[1-(4-phenyl-2-thiazolyl)-4-piperidinyl]amine from 2-bromoacetophenone, and b) 1-[1-[4-chlorophenyl)-2-thiazolyl]-4-piperidinyl]amine from 2-bromo-4xe2x80x2-chloroacetophenone.
The compounds of formula I having basic groups can be converted into acid addition salts, especially pharmaceutically acceptable acid addition salts. For example, the free base of a compound of formula I can be reacted with hydrochloric acid in gaseous form to form the corresponding mono- and di-hydrochloride salt forms, whereas reacting the free base with methanesulfonic acid forms the corresponding mesylate salt form. All pharmaceutically acceptable acid addition salt forms of the compounds of formula I are intended to be embraced by the scope of this invention.
In view of the close relationship between the free compounds and the compounds in the form of their salts, whenever a compound is referred to in this context, a corresponding salt is also intended, provided such is possible or appropriate under the circumstances.
The compounds, including their salts, can also be obtained in the form of their hydrates, or include other solvents used for their crystallization.
As indicated above, all of the compounds of formula I, and their corresponding pharmaceutically acceptable acid addition salts, are useful in inhibiting DPP-IV. The ability of the compounds of formula I, and their corresponding pharmaceutically acceptable acid addition salts, to inhibit DPP-IV may be demonstrated employing the Caco-2 DPP-IV Assay which measures the ability of test compounds to inhibit DPP-IV activity from human colonic carcinoma cell extracts. The human colonic carcinoma cell line Caco-2 was obtained from the American Type Culture Collection (ATCC HTB 37). Differentiation of the cells to induce DPP-IV expression was accomplished as described by Reisher, et al. in an article entitled xe2x80x9cIncreased expression of intestinal cell line Caco-2xe2x80x9d in Proc. Natl. Acad. Sci., Vol. 90, pgs. 5757-5761 (1993). Cell extract is prepared from cells solubilized in 10 mM Tris HCl, 0.15 M NaCl, 0.04 t.i.u.aprotinin, 0.5% nonidet-P40, pH 8.0, which is centrifuged at 35,000 g for 30 min. at 4xc2x0 C. to remove cell debris. The assay is conducted by adding 20 xcexcg solubilized Caco-2 protein, diluted to a final volume of 125 xcexcl in assay buffer (25 mM Tris HCl pH 7.4, 140 mM NaCl, 10 mM KCl, 1% bovine serum albumin) to microtiter plate wells. After a 60 min. incubation at room temperature, the reaction is initiated by adding 25 xcexcl of 1 mM substrate (H-Alanine-Proline-pNA; pNA is p-nitroaniline). The reaction is carried out at room temperature for 10 minutes after which time a 19 xcexcl volume of 25% glacial acetic acid is added to stop the reaction. Test compounds are typically added as 30 xcexcl additions and the assay buffer volume is reduced to 95 xcexcl. A standard curve of free p-nitroaniline is generated using 0-500 xcexcM solutions of free pNA in assay buffer. The curve generated is linear and is used for interpolation of substrate consumption (catalytic activity in nmoles substrate cleaved/min). The endpoint is determined by measuring absorbance at 405 nm in a Molecular Devices UV Max microtiter plate reader.
The potency of the test compounds as DPP-IV inhibitors, expressed as IC50, is calculated from 8-point, dose-response curves using a 4-parameter logistic function.
The following IC50""s were obtained:
The ability of the compounds of formula I, and their corresponding pharmaceutically acceptable acid addition salts, to inhibit DPP-IV may also be demonstrated by measuring the effects of test compounds on DPP-IV activity in human and rat plasma employing a modified version of the assay described by Kubota, et al. in an article entitled xe2x80x9cInvolvement of dipeptidylpeptidase IV in an in vivo immune responsexe2x80x9d in Clin. Exp. Immunol., Vol. 89, pgs. 192-197 (1992). Briefly, 5 xcexcl of plasma are added to 96-well flat-bottom micortiter plates (Falcon), followed by the addition of 5 xcexcl of 80 mM MgCl2 in incubation buffer (25 mMHEPES, 140 mM NaCl, 1% RIA-grade BSA, pH 7.8). After a 60 min. incubation at room temperature, the reaction is initiated by the addition of 10 xcexcl of incubation buffer containing 0.1 mM substrate (H-Glycine-Proline-AMC; AMC is 7-amino 4-methylcoumarin). The plates are covered with aluminum foil (or kept in the dark) and incubated at room temperature for 20 min. After the 20 min. reaction, florescence is measured using a CytoFluor 2350 fluorimeter (Excitation 380 mn Emission 460 nm; sensitivity setting 4). Test compounds are typically added as 2 xcexcl additions and the assay buffer volume is reduced to 13 xcexcl. A fluorescence-concentration curve of free AMC is generated using 0-50 xcexcM solutions of AMC in assay buffer. The curve generated is linear and is used for interpolation of substrate consumption (catalytic activity in nmoles substrate cleaved/min). As with the previous assay, the potency of the test compounds as DPP-IV inhibitors, expressed as IC50, is calculated from 8-point, dose-response curves using a 4 parameter logistic function.
The following IC50""s were obtained:
In view of their ability to inhibit DPP-IV, the compounds of formula I, and their corresponding pharmaceutically acceptable acid addition salts, are useful in treating conditions mediated by DPP-IV inhibition. Based on the above and findings in the literature, it is expected that the compounds disclosed herein are useful in the treatment of conditions such as non-insulin-dependent diabetes mellitus, arthritis, obesity, allograft transplantation and calcitonin-osteoporosis. In addition, based on the roles of glucagon-like peptides (such as GLP-1 and GLP-2) and their association with DPP-IV inhibition, it is expected that the compounds disclosed herein are useful for example, to produce a sedative or anxiolytic effect, or to attenuate post-surgical catabolic changes and hormonal responses to stress, or to reduce mortality and morbidity after myocardial infarction, or in the treatment of conditions related to the above effects which may be mediated by GLP-1 and/or GLP-2 levels.
More specifically, for example, the compounds of formula I, and their corresponding pharmaceutically acceptable acid addition salts, improve early insulin response to an oral glucose challenge and, therefore, are useful in treating non-insulin-dependent diabetes mellitus. The ability of the compounds of formula I, and their corresponding pharmaceutically acceptable acid addition salts, to improve early insulin response to an oral glucose challenge may be measured in insulin resistant rats according to the following method:
Male Sprague-Dawley rats that had been fed a high fat diet (saturated fat=57% calories) for 2-3 weeks were fasted for approximately 2 hours on the day of testing, divided into groups of 7-10, and dosed orally with 10 xcexcmol/kg of test compound in carboxymethylcellulose. Each of the test compounds administered orally at 10 xcexcmol/kg ten minutes prior to the administration of glucose (1 g/kg p.o.), led to a significant inhibition of plasma DPP-IV activity during the study. For example, the compound of Example 2N, administered orally at 10 xcexcmol/kg (n=7-8) ten minutes prior to the administration of glucose (1 g/kg p.o.), led to an 80% inhibition of plasma DPP-IV activity during the study. Blood samples, obtained at various time-points from chronic jugular vein catheters, were analyzed for plasma glucose concentration. Data are expressed as % decrease of the area under the plasma glucose curve compared to vehicle-treated control animals. The following result was obtained:
The precise dosage of the compounds of formula I, and their corresponding pharmaceutically acceptable acid addition salts, to be employed for treating conditions mediated by DPP-IV inhibition depends upon several factors, including the host, the nature and the severity of the condition being treated, the mode of administration and the particular compound employed. However, in general, conditions mediated by DPP-IV inhibition are effectively treated when a compound of formula I, or a corresponding pharmaceutically acceptable acid addition salt, is administered enterally, e.g., orally, or parenterally, e.g., intravenously, preferably orally, at a daily dosage of 0.002-5, preferably 0.02-2.5 mg/kg body weight or, for most larger primates, a daily dosage of 0.1-250, preferably 1-100 mg. A typical oral dosage unit is 0.01-0.75 mg/kg, one to three times a day. Usually, a small dose is administered initially and the dosage is gradually increased until the optimal dosage for the host under treatment is determined. The upper limit of dosage is that imposed by side effects and can be determined by trial for the host being treated.
The compounds of formula I, and their corresponding pharmaceutically acceptable acid addition salts, may be combined with one or more pharmaceutically acceptable carriers and, optionally, one or more other conventional pharmaceutical adjuvants and administered enterally, e.g., orally, in the form of tablets, capsules, caplets, etc. or parenterally, e.g., intravenously, in the form of sterile injectable solutions or suspensions. The enteral and parenteral compositions may be prepared by conventional means.
The compounds of formula I, and their corresponding pharmaceutically acceptable acid addition salts, may be formulated into enteral and parenteral pharmaceutical compositions containing an amount of the active substance that is effective for treating conditions mediated by DPP-IV inhibition, such compositions in unit dosage form and such compositions comprising a pharmaceutically acceptable carrier.
The compounds of formula I (including those of each of the subscopes thereof and each of the examples) may be administered in enantiomerically pure form (e.g., ee greater than 98%, preferably greater than 99%) or together with the R enantiomer, e.g., in racemic form. The above dosage ranges are based on the compounds of formula I (excluding the amount of the R enantiomer).
The present invention furthermore refers to a combination, especially a combined preparation or pharmaceutical composition, respectively, comprising a compound of formula I or a pharmaceutically acceptable acid addition salt thereof and at least one different antidiabetic agent (e.g. one or two different antidiabetic agents) or a pharmaceutically acceptable salt thereof.
A suitable antidiabetic agent is e.g. selected from the group consisting of insulin signalling pathway modulators, like inhibitors of protein tyrosine phosphatases (PTPases), non-small molecule mimetic compounds and inhibitors of glutamine-fructose-6-phosphate amidotransferase (GFAT), compounds influencing a dysregulated hepatic glucose production, like inhibitors of glucose-6-phosphatase (G6Pase), inhibitors of fructose-1,6-bisphosphatase (F-1,6-BPase), inhibitors of glycogen phosphorylase (GP), glucagon receptor antagonists and inhibitors of phosphoenolpyruvate carboxykinase (PEPCK), pyruvate dehydrogenase kinase (PDHK) inhibitors, insulin sensitivity enhancers, insulin secretion enhancers, xcex1-glucosidase inhibitors, inhibitors of gastric emptying, insulin, and xcex12-adrenergic antagonists for simultaneous, separate or sequential use.
Examples of xe2x80x9cinhibitors of PTPasexe2x80x9d include, but are not limited to those disclosed in U.S. Pat. Nos. 6,057,316, 6,001,867, WO 99/58518, WO 99/58522, WO 99/46268, WO 99/46267, WO 99/46244, WO 99/46237, WO 99/46236, WO 99/15529 and by Poucheret et al in Mol. Cell Biochem. 1998, 188, 73-80.
Examples of xe2x80x9cnon-small molecule mimetic compoundsxe2x80x9d include, but are not limited to those disclosed in Science 1999, 284; 974-97, especially L-783,281, and WO 99/58127, especially CLX-901.
Examples of xe2x80x9cinhibitors of GFATxe2x80x9d include, but are not limited to those disclosed in Mol. Cell. Endocrinol. 1997, 135(1), 67-77.
The term xe2x80x9cinhibitors of G6Pasexe2x80x9d used herein means a compound or composition which reduces or inhibits hepatic gluconeogenesis by decreasing or inhibiting the activity of G6Pase. Examples of such compounds are disclosed in WO 00/14090, WO 99/40062, WO 98/40385, EP682024 and Diabetes 1998, 47, 1630-1636.
The term xe2x80x9cinhibitors of F-1,6-BPasexe2x80x9d used herein means a compound or composition which reduces or inhibits hepatic gluconeogenesis by decreasing or inhibiting the activity of F-1,6-BPase. Examples of such compounds are disclosed in WO 00/14095, WO 99/47549, WO 98/39344, WO 98/39343 and WO 98/39342.
The term xe2x80x9cinhibitors of GPxe2x80x9d used herein means a compound or composition which reduces or inhibits hepatic glycogenolysis by decreasing or inhibiting the activity of GP. Examples of such compounds are disclosed in EP 978279, U.S. Pat. No. 5,998,463, WO 99/26659, EP 846464, WO 97/31901, WO 96/39384, WO9639385 and in particular CP-91149 as described in Proc. Natl. Acad Sci USA 1998, 95, 1776-1781.
The term xe2x80x9cglucagon receptor antagonistsxe2x80x9d as used herein relates in particular to the compounds described in WO 98/04528, especially BAY27-9955, and those described in Bioorg Med. Chem. Lett 1992, 2, 915-918, especially CP-99,711, J. Med. Chem. 1998, 41, 5150-5157, especially NNC 92-1687, and J. Biol Chem. 1999, 274; 8694-8697, especially L-168,049 and compounds disclosed in U.S. Pat. No. 5,880,139, WO 99/01423, U.S. Pat. No. 5,776,954, WO 98/22109, WO 98/22108, WO 98/21957 and WO 97/16442.
The term xe2x80x9cinhibitors of PEPCKxe2x80x9d used herein means a compound or composition which reduces or inhibits hepatic gluconeogenesis by decreasing or inhibiting the activity of PEPCK. Examples of such compounds are disclosed in U.S. Pat. No. 6,030,837 and Mol. Biol. Diabetes 1994 2 283-99.
The term xe2x80x9cPDHK inhibitorsxe2x80x9d as used herein means inhibitors of pyruvate dehydrogenase kinase and include, but are not limited to, those compounds disclosed by Aicher et al in J. Med. Chem. 42 (1999) 2741-2746.
The term xe2x80x9cinsulin sensitivity enhancerxe2x80x9d used herein means any and all pharmacological active compounds that enhance the tissue sensitivity towards insulin. Insulin sensitivity enhancers include, e.g., inhibitors of GSK-3, retinoid X receptor (RXR) agonists, agonists of Beta-3 AR, agonists of UCPs, antidiabetic thiazolidinediones (glitazones), non-glitazone type PPARxcex3 agonists, dual PPARxcex3/PPARxcex1 agonists, antidiabetic vanadium containing compounds and biguanides, e.g., metformin.
The insulin sensitivity enhancer is preferably selected from the group consisting of antidiabetic thiazolidinediones, antidiabetic vanadium containing compounds and metformin.
In one preferred embodiment, the insulin sensitivity enhancer is metformin.
Examples of xe2x80x9cinhibitors of GSK-3xe2x80x9d include, but are not limited to those disclosed in WO 00/21927 and WO 97/41854.
By xe2x80x9cRXR agonistxe2x80x9d is meant a compound or composition which when combined with RXR homodimers or heterodimers increases the transcriptional regulation activity of RXR, as measured by an assay known to one skilled in the art, including, but not limited to, the xe2x80x9cco-transfectionxe2x80x9d or xe2x80x9ccis-transxe2x80x9d assays described or disclosed in U.S. Pat. Nos. 4,981,784, 5,071,773, 5,298,429, 5,506,102, WO89/05355, WO91/06677, WO92/05447, WO93/11235, WO95/18380, PCT/US93/04399, PCT/US94103795 and CA 2,034,220, which are incorporated by reference herein. It includes, but is not limited to, compounds that preferentially activate RXR over RAR (i.e. RXR specific agonists), and compounds that activate both RXR and RAR (i.e. pan agonists). It also includes compounds that activate RXR in a certain cellular context but not others (i.e. partial agonists). Compounds disclosed or described in the following articles, patents and patent applications which have RXR agonist activity are incorporated by reference herein: U.S. Pat. Nos. 5,399,586 and 5,466,861, WO96/05165, PCT/US95/16842, PCT/US95/16695, PCT/US93/10094, WO94/15901, PCT/US92/11214, WO93/11755, PCT/US93/10166, PCT/US93/10204, WO094/15902, PCT/US93/03944, WO93/21146, provisional applications No. 60,004,897 and No. 60,009,884, Boehm, et al. J. Med. Chem. 38(16):3146-3155, 1994, Boehm, et al. J. Med. Chem. 37(18):2930-2941, 1994, Antras et al., J. Biol. Chem. 266:1157-1161 (1991), Salazar-Olivo et al., Biochem. Biophys. Res. Commun. 204:157-263 (1994) and Safanova, Mol. Cell. Endocrin. 104:201-211 (1994). RXR specific agonists include, but are not limited to, LG 100268 (i.e. 2-[1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-cyclopropyl]-pyridine-5-carboxylic acid) and LGD 1069 (i.e. 4-[(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-2-carbonyl]-benzoic acid), and analogs, derivatives and pharmaceutically acceptable salts thereof. The structures and syntheses of LG 100268 and LGD 1069 are disclosed in Boehm, et al. J. Med. Chem. 38(16): 3146-3155, 1994, incorporated by reference herein. Pan agonists include, but are not limited to, ALRT 1057 (i.e. 9-cis retinoic acid), and analogs, derivatives and pharmaceutically acceptable salts thereof.
Examples of xe2x80x9cagonists of Beta-3 ARxe2x80x9d include, but are not limited to CL-316,243 (Lederle Laboratories) and those disclosed in WO 99/29672, WO 98/32753, WO 98/20005, WO 98/09625, WO 97/46556, WO 97/37646 and U.S. Pat. No. 5,705,515.
The term xe2x80x9cagonists of UCPsxe2x80x9d used herein means agonists of UCP-1, preferably UCP-2 and even more preferably UCP-3. UCPs are disclosed in Vidal-Puig et al., Biochem. Biophys. Res. Commun., Vol. 235(1) pp. 79-82 (1997). Such agonists are a compound or composition which increases the activity of UCPs.
The antidiabetic thiazolidinedione (glitazone) is, for example, (S)-((3,4-dihydro-2-(phenyl-methyl)-2H-1-benzopyran-6-yl)methyl-thiazolidine-2,4-dione (englitazone), 5-{[4-(3-(5-methyl-2-phenyl-4-oxazolyl)-1-oxopropyl)-phenyl]-methyl}-thiazolidine-2,4-dione (darglitazone), 5-{[4-(1-methyl-cyclohexyl)methoxy)-phenyl]methyl}-thiazolidine-2,4-dione (ciglitazone), 5-{[4-(2-(1-indolyl)ethoxy)phenyl]methyl}-thiazolidine-2,4-dione (DRF2189), 5-{4-[2-(5methyl-2phenyl-4-oxazolyl)-ethoxy)]benzyl}-thiazolidine-2,4-dione (BM-13.1246), 5-(2-naphthylsulfonyl)-thiazolidine-2,4-dione (AY-31637), bis{4-[(2,4-dioxo-5-thiazolidinyl)methyl]phenyl}methane (YM268), 5-{4-[2-(5-methyl-2-phenyl-4-oxazolyl)-2-hydroxyethoxy]benzyl}-thiazolidine-2,4-dione (AD-5075), 5-[4-(1-phenyl-1-cyclopropanecarbonylamino)-benzyl]-thiazolidine-2,4-dione (DN-108) 5-{[4-(2-(2,3-dihydroindol-1-yl)ethoxy)phenylmethyl}-thiazolidine-2,4-dione, 5-[3-(4-chloro-phenyl])-2-propynyl]-5-phenylsulfonyl)thiazolidine-2,4-dione, 5-[3-(4-chlorophenyl])-2-propynyl]-5-(4-fluorophenylsulfonyl)thiazolidine-2,4-dione, 5-{[4-(2-(methyl-2-pyridinyl-amino)-ethoxy)phenyl]methyl}thiazolidine-2,4-dione (rosiglitazone), 5-{[4-(2-(5-ethyl-2-pyridyl)ethoxy)phenyl]-methyl}thiazolidine-2,4-dione (pioglitazone), 5-{[4-((3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)methoxy)-phenyl]-methyl}-thiazolidine-2,4-dione (troglitazone), 5-[6-(2-fluoro-benzyloxy)-naphthalen-2-ylmethyl]-thiazolidine-2,4-dione (MCC555), 5-{[2-(2-naphthyl)-benzoxazol-5-yl]-methyl}thiazolidine-2,4-dione (T-174) and 5-(2,4-dioxothiazolidin-5-ylmethyl)-2-methoxy-N-(4-trifluoromethyl-benzyl)benzamide (KRP297).
The glitazones 5-{[4-(2-(5-ethyl-2-pyridyl)ethoxy)phenyl]-methyl}thiazolidine-2,4-dione (pioglitazone, EP 0 193 256 A1), 5-{[4-(2-(methyl-2-pyridinyl-amino)-ethoxy)phenyl]methyl}-thiazolidine-2,4-dione (rosiglitazone, EP 0 306 228 A1), 5-{[4-((3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)methoxy)-phenyl]-methyl}thiazolidine-2,4-dione (troglitazone, EP 0 139 421), (S)-((3,4-dihydro-2-(phenyl-methyl)-2H-1-benzopyran-6-yl)methyl-thiazolidine-2,4-dione (englitazone, EP 0 207 605 B1), 5-(2,4-dioxothiazolidin-5-ylmethyl)-2-methoxy-N-(4-trifluoromethyl-benzyl)benzamide (KRP297, JP 10087641-A), 5-[6-(2-fluoro-benzyloxy)naphthalen-2-ylmethyl]thiazolidine-2,4-dione (MCC555, EP 0 604 983 B1), 5-{[4-(3-(5-methyl-2-phenyl-4-oxazolyl)-1-oxopropyl)-phenyl]-methyl}-thiazolidine-2,4-dione (darglitazone, EP 0 332 332), 5-(2-naphthylsulfonyl)-thiazolidine-2,4-dione (AY-31637, U.S. Pat. No. 4,997,948), 5-{[4-(1-methyl-cyclohexyl)methoxy)-phenyl]methyl}-thiazolidine-2,4-dione (ciglitazone, U.S. Pat. No. 4,287,200) are in each case generically and specifically disclosed in the documents cited in brackets beyond each substance, in each case in particular in the compound claims and the final products of the working examples, the subject-matter of the final products, the pharmaceutical preparations and the claims are hereby incorporated into the present application by reference to these publications. The preparation of DRF2189 and of 5-{[4-(2-(2,3-dihydroindol-1-yl)ethoxy)phenyl]methyl}-thiazolidine-2,4-dione is described in B. B. Lohray et al., J. Med. Chem. 1998, 41, 1619-1630; Examples 2d and 3g on pages 1627 and 1628. The preparation of 5-[3-(4-chlorophenyl])-2-propynyl]-5-phenylsulfonyl)-thiazolidine-2,4-dione and the other compounds in which A is phenylethynyl mentioned herein can be carried out according to the methods described in J. Wrobel et al., J. Med. Chem. 1998, 41,1084-1091.
In particular, MCC555 can be formulated as disclosed on page 49, lines 30 to 45, of EP 0 604 983 B1; englitazone as disclosed from page 6, line 52, to page 7, line 6, or analogous to Examples 27 or 28 on page 24 of EP 0 207 605 B1; and darglitazone and 5-{4-[2-(5-methyl-2-phenyl-4-oxazolyl)-ethoxy)]benzyl}-thiazolidine-2,4-dione (BM-13.1246) can be formulated as disclosed on page 8, line 42 to line 54 of EP 0 332 332 B1. AY-31637 can be administered as disclosed in column 4, lines 32 to 51 of U.S. Pat. No. 4,997,948 and rosiglitazone as disclosed on page 9, lines 32 to 40 of EP 0 306 228 A1, the latter preferably as its maleate salt. Rosiglitazone can be administered in the form as it is marketed e.g. under the trademark AVANDIA(trademark). Troglitazone can be administered in the form as it is marketed e.g. under the trademarks ReZulinr(trademark), PRELAY(trademark), ROMOZIN(trademark) (in the United Kingdom) or NOSCAL(trademark) (in Japan). Pioglitazone can be administered as disclosed in Example 2 of EP 0 193 256 A1, preferably in the form of the monohydrochloride salt. Corresponding to the needs of the single patient it can be possible to administer pioglitazone in the form as it is marketed e.g. under the trademark ACTOS(trademark). Ciglitazone can, for example, be formulated as disclosed in Example 13 of U.S. Pat. No. 4,287,200.
Non-glitazone type PPARxcex3 agonists are especially N-(2-benzoylphenyl)-L-tyrosine analogues, e.g. GI-262570, and JTT501.
The term xe2x80x9cdual PPARxcex3/PPARxcex1 agonistsxe2x80x9d as used herein means compounds which are at the same time PPARxcex3 and PPARxcex1 agonists. Preferred dual PPARxcex3/PPARxcex1 agonists are especially those xcfx89-[(oxoquinazolinylalkoxy)phenyl]alkanoates and analogs thereof, very especially the compound DRF-554158, described in WO 99/08501 and the compound NC-2100 described by Fukui in Diabetes 2000, 49(5), 759-767.
Preferably, the antidiabetic vanadium containing compound is a physiologically tolerable vanadium complex of a bidentate monoprotic chelant, wherein said chelant is an a-hydroxypyrone or xcex1-hydroxypyridinone, especially those disclosed in the Examples of U.S. Pat. No. 5,866,563, of which the working examples are hereby incorporated by reference, or a pharmaceutically acceptable salt thereof.
The preparation of metformin (dimethyldiguanide) and its hydrochloride salt is state of the art and was disclosed first by Emil A. Werner and James Bell, J. Chem. Soc. 121, 1922, 1790-1794. Metformin, can be administered e.g. in the form as marketed under the trademarks GLUCOPHAGE(trademark).
Insulin secretion enhancers are pharmacological active compounds having the property to promote secretion of insulin from pancreatic xcex2 cells. Examples for insulin secretion enhancers include glucagon receptor antagonists (see above), sulphonyl urea derivatives, incretin hormones, especially glucagon-like peptide-1 (GLP-1) or GLP-1 agonists, xcex2-cell imidazoline receptor antagonists, and short-acting insulin secretagogues, like antidiabetic phenylacetic acid derivatives, antidiabetic D-phenylalanine derivatives and BTS 67582 described by T. Page et al in Br. J. Pharmacol. 1997, 122, 1464-1468.
The sulphonyl urea derivative is, for example, glisoxepid, glyburide, glibenclamide, acetohexamide, chloropropamide, glibornuride, tolbutamide, tolazamide, glipizide, carbutamide, gliquidone, glyhexamide, phenbutamide or tolcyclamide; and preferably glimepiride or gliclazide. Tolbutamide, glibenclamide, gliclazide, glibornuride, gliquidone, glisoxepid and glimepiride can be administered e.g. in the form as they are marketed under the trademarks RASTINON HOECHST(trademark), AZUGLUCON(trademark), DIAMICRON(trademark), GLUBORID(trademark), GLURENORM(trademark), PRO-DIABAN(trademark) and AMARYL(trademark), respectively.
GLP-1 is a insulinotropic proteine which was described, e.g., by W. E. Schmidt et al. in Diabetologia 28, 1985, 704-707 and in U.S. Pat. No. 5,705,483. The term xe2x80x9cGLP-1 agonistsxe2x80x9d used herein means variants and analogs of GLP-1(7-36)NH2 which are disclosed in particular in U.S. Pat. Nos. 5,120,712, 5,118,666, 5,512,549, WO 91/11457 and by C. Orskov et al in J. Biol. Chem. 264 (1989) 12826. The term xe2x80x9cGLP-1 agonistsxe2x80x9d comprises especially compounds like GLP-1(7-37), in which compound the carboxy-terminal amide functionality of Arg36 is displaced with Gly at the 37th position of the GLP-1(7-36)NH2 molecule and variants and analogs thereof including GLN9-GLP-1(7-37), D-GLN9-GLP-1(7-37), acetyl LYS9-GLP-1(7-37), LYS18-GLP-1(7-37) and, in particular, GLP-1(7-37)OH, VAL8-GLP-1(7-37), GLY8-GLP-1(7-37), THR8-GLP-1(7-37) imidazopropionyl-GLP-1. Special preference is also given to the GLP agonist analog exendin-4, described by Greig et al in Diabetologia 1999, 42, 45-50.
The term xe2x80x9cxcex2-cell imidazoline receptor antagonistsxe2x80x9d as used herein means compounds as those described in WO 00/78726 and by Wang et al in J. Pharmacol. Exp. Ther. 1996; 278; 82-89, e.g. PMS 812.
The antidiabetic phenylacetic acid derivative is preferably repaglinide or a pharmaceutically acceptable salt thereof.
Most preferably, the antidiabetic D-phenylalanine derivative is nateglinide or a pharmaceutically acceptable salt thereof.
Nateglinide (N-[(trans-4-isopropylcyclohexyl)-carbonyl]-D-phenylalanine, EP 196222 and EP 526171) and repaglinide ((S)-2-ethoxy-4-{2-[[3-methyl-1-[2-(1-piperidinyl)phenyl]butyl]amino]-2-oxoethyl}benzoic acid, EP 0 147 850 A2, in particular Example 11 on page 61, and EP 0 207 331 A1) are in each case generically and specifically disclosed in the documents cited in brackets beyond each substance, in each case in particular in the compound claims and the final products of the working examples, the subject-matter of the final products, the pharmaceutical preparations and the claims are hereby incorporated into the present application by reference to these publications. The term nateglinide as used herein comprises crystal modifications (polymorphs) such as those disclosed in EP 0526171 B1 or U.S. Pat. No. 5,488,510, respectively, the subject matter of which is incorporated by reference to this application, especially the subject matter of claims 8 to 10 as well as the corresponding references to the B-type crystal modification. Preferably, in the present invention the B- or H-type, more preferably the H-type, is used. Repaglinde can be administered in the form as it is marketed e.g. under the trademark NovoNorm(trademark). Nateglinide can be administered in the form as it is marketed e.g. under the trademark STARLIX(trademark).
xcex1-Glucosidase inhibitors are pharmacological active compounds which inhibit small intestinal xe2x96xa1-glucosidase enzymes which break down non-adsorbable complex carbohydrates into absorbable monosaccharides. Examples for such compounds are acarbose, N-(1,3-dihydroxy-2-propyl)valiolamine (voglibose) and the 1-deoxynojirimycin derivative miglitol. Acarbose is 4xe2x80x3,6xe2x80x3-dideoxy-4xe2x80x3-[(1S)-(1,4,6/5)-4,5,6-trihydroxy-3-hydroxymethyl-2-cyclo-hexenylaminolmaltotriose. The structure of acarbose can as well be described as O-4,6-dideoxy-4-{[1S,4R,5S,6S]-4,5,6-trihydroxy-3-(hydroxymethyl)-2-cyclohexen-1-yl]-amino}-xcex1-D-glucopyranosyl-(1xe2x86x924)-O-xcex1-D-glucopyranosyl-(1xe2x86x924)-D-glucopyranose. Acarbose (U.S. Pat. No. 4,062,950 and EP 0 226 121), is generically and specifically disclosed in the documents cited in brackets, in particular in the compound claims and the final products of the working examples, the subject-matter of the final products, the pharmaceutical preparations and the claims are hereby incorporated into the present application by reference to these publications. Corresponding to the needs of the single patient it can be possible to administer acarbose in the form as it is marketed e.g. under the trademark GLUCOBAY(trademark). Miglitol can be administered in the form as it is marketed e.g. under the trademark DIASTABOL 50(trademark).
The xe2x96xa1-glucosidase inhibitor is preferably selected from the group consisting of acarbose, voglibose and miglitol.
Examples of xe2x80x9cinhibitors of gastric emptyingxe2x80x9d other than GLP-1 include, but are not limited to those disclosed in J. Clin. Endocrinol. Metab. 2000, 85(3), 1043-1048, especially CCK-8, and in Diabetes Care 1998; 21; 897-893, especially Amylin and analogs thereof, e.g. Pramlintide. Amylin is also described e.g. by O. G. Kolterman et al. in Diabetologia 39, 1996, 492-499.
Examples of xe2x80x9cxcex12-adrenergic antagonistsxe2x80x9d include, but are not limited to midaglizole described in Diabetes 36, 1987, 216-220.
Comprised are likewise the corresponding stereoisomers as well as the corresponding polymorphs, e.g. crystal modifications, which are disclosed in the cited patent documents.
In a very preferred embodiment of the invention, the further antidiabetic compound is selected from the group consisting of nateglinide, repaglinide, metformin, rosiglitazone, pioglitazone, troglitazone, glisoxepid, glyburide, glibenclamide, acetohexamide, chloropropamide, glibomuride, tolbutamide, tolazamide, glipizide, carbutamide, gliquidone, glyhexamide, phenbutamide, tolcyclamide, glimepiride and gliclazide, or the pharmaceutically acceptable salt of such a compound. Most preferred is nateglinide, repaglinide or metformin, respectively, furthermore, pioglitazone, rosiglitazone or troglitazone respectively.
The structure of the active agents identified by code nos., generic or trade names may be taken from the actual edition of the standard compendium xe2x80x9cThe Merck Indexxe2x80x9d or from databases, e.g. Patents International (e.g. IMS World Publications). The corresponding content thereof is hereby incorporated by reference. Any person skilled in the art is fully enabled to identify the active agents and, based on these references, likewise enabled to manufacture and test the pharmaceutical indications and properties in standard test models, both in vitro and in vivo.
The combinations according to the present invention can used especially in the prevention, delay of progression or treatment of conditions mediated by dipeptidylpeptidase-IV (DPP-IV), in particular diabetes, more particular type 2 diabetes mellitus, conditions of impaired glucose tolerance (IGT), conditions of impaired fasting plasma glucose, metabolic acidosis, ketosis, arthritis, obesity and osteoporosis; for the prevention, delay of progression or treatment of such conditions; the use of such combination for the cosmetic treatment of a mammal in order to effect a cosmetically beneficial loss of body weight.
The person skilled in the pertinent art is fully enabled to select a relevant animal test model to prove the hereinbefore and hereinafter indicated therapeutic indications and beneficial effects.
The invention furthermore relates to a commercial package comprising a compound according to the present invention or a combination according to the present invention together with instructions for simultaneous, separate or sequential use
The following examples show representative compounds encompassed by this invention and their synthesis. However, it should be clearly understood that they are for purposes of illustration only.